Biology subjects

Kersten, K.

Publications and source records attributed to Kersten, K..

8 recordsLinked to original sources

bioRxiv2026

Disruption of the ARID1A-containing SWI/SNF complex reprograms tumor-associated macrophages and enhances immunotherapy response

Tumor-associated macrophages (TAMs) contribute to tumor immune evasion and therapeutic resistance. However, the epigenetic and transcriptional regulators that control TAM function remain largely unidentified. Here we investigated the role of the SWI/SNF chromatin remodeling complex in TAMs and whether disruption of SWI/SNF function in TAMs could improve immunotherapy. Pharmacologic inhibition of SWI/SNF ATPase activity improved the efficacy of checkpoint blockade immunotherapy, slowing tumor growth and reprogramming transcription broadly in tumor cells, tumor-infiltrating lymphocytes, and TAMs. To define the role of SWI/SNF in TAMs specifically, we genetically deleted the SWI/SNF subunit Arid1a in myeloid cells and found this was sufficient to suppress tumor progression and enhance checkpoint blockade response. Epigenomic and single cell analyses indicated that SWI/SNF inhibition and ARID1A deletion in TAMs reduced accessibility at enhancers of genes associated with poor prognosis, such as Spp1, and increased accessibility at promoters of interferon-stimulated genes (ISGs). CD86 was elevated on ARID1A-deficient TAMs and the enhanced immunotherapy response required CD86 costimulation and CD8+ T cells. These findings establish ARID1A-dependent chromatin remodeling as a determinant of TAM gene expression programs and show that disruption of myeloid SWI/SNF function improves checkpoint blockade immunotherapy via TAM reprogramming.

cancer biology↗

bioRxiv2025

NCOR2 represses MHC class I molecule expression to drive metastatic progression of breast cancer

Metastatic progression depends upon the ability of disseminated tumor cells to evade immune surveillance. MHC molecule expression facilitates T cell recognition and activation to permit the eradication of metastatic tumor cells. We identified nuclear corepressor 2 (NCOR2) as a key epigenetic regulator of MHC class I molecule expression on breast tumor cells. Patients with triple negative breast cancers (TNBC) that expressed high levels of NCOR2 also exhibited reduced metastasis free survival and decreased MHC class I expression, and the metastatic lesions in patients with TNBC had high nuclear NCOR2 and reduced CD8 T cell levels and activity. Genetically and experimentally reducing NCOR2 expression in tumor cells permitted interferon gamma upregulation of MHC class I, and potentiated CD8 T cell activity and induction of apoptosis to repress metastatic progression of disseminated breast cancer cells. These studies provide evidence to support NCOR2 as a targetable epigenetic regulator of metastasis towards which therapies could be developed to reduce patient mortality.

cancer biology↗

bioRxiv2023

Critical role of CD206+ macrophages in organizing anti-tumor immunity

Tumor-associated macrophages (TAMs) are frequently categorized as being M1 or M2 polarized, even as substantial data challenges this binary modeling of macrophage cell state. One molecule consistently referenced as a delineator of a putative immunosuppressive M2 state is the surface protein CD206. We thus made a novel conditional CD206 (Mrc1) knock-in mouse to specifically visualize and/or deplete CD206+ M2-like TAMs and assess their correspondence with pro-tumoral immunity. Early, but not late depletion of CD206+ macrophages and monocytes (here, Mono/Macs) led to an indirect loss of a key anti-tumor network of NK cells, conventional type I dendritic cells (cDC1) and CD8 T cells. Among myeloid cells, we found that the CD206+ TAMs are the primary producers of CXCL9, and able to differentially attract activated CD8 T cells. In contrast, a population of stress-responsive TAMs ("Hypoxic" or Spp1+) and immature monocytes, which lack CD206 expression and become prominent following early depletion, expressed markedly diminished levels of CXCL9. Those NK and CD8 T cells which enter CD206- depleted tumors express vastly reduced levels of the corresponding receptor Cxcr3, the cDC1- attracting chemokine Xcl1 and cDC1 growth factor Flt3l transcripts. Consistent with the loss of this critical network, early CD206+ TAM depletion decreased tumor control by antigen specific CD8 T cells in mice. Likewise, in humans, the CD206Replete, but not the CD206Depleted Mono/Mac gene signature correlated robustly with CD8 T cell, NK cell and stimulatory cDC1 gene signatures and transcriptomic signatures skewed towards CD206Replete Mono/Macs associated with better survival. Together, these findings negate the unqualified classification of CD206+ M2-like macrophages as immunosuppressive by illuminating contexts for their role in organizing a critical tumor-reactive archetype of immunity.

immunology↗

bioRxiv2022

Uptake of tumor-derived microparticles induces metabolic reprogramming of macrophages in the early metastatic lung.

The formation of a pre-metastatic niche is a critical step during the metastatic spread of cancer. One way by which primary tumors prime host cells at future metastatic sites is through local shedding of tumor-derived microparticles as a consequence of vascular sheer flow. However, it remains unclear how the uptake of such particles by resident immune cells affects their phenotype and function. Here we show that ingestion of tumor-derived microparticles by macrophages induces a rapid metabolic and phenotypic switch that is characterized by enhanced mitochondrial mass and function, increased oxidative phosphorylation and upregulation of cellular adhesion molecules resulting in reduced motility in the early metastatic lung. We show that this reprogramming event is dependent on signaling through the mTORC1, but not mTORC2 pathway, and is unique to uptake of tumor-derived microparticles. Together, these data support a mechanism by which uptake of tumor-derived microparticles induces reprogramming of macrophages to shape their fate and function in the early metastatic lung.

immunology↗

bioRxiv2022

Myeloid mechano-metabolic programming restricts anti-tumor immunity

Tumor progression is accompanied by fibrosis, which is associated with diminished anti-tumor immune infiltrate. Here, we demonstrate that tumor infiltrating myeloid cells respond to the stiffened fibrotic tumor microenvironment (TME) by initiating a TGF-beta (TGF{beta})-directed, collagen biosynthesis program. A collateral effect of this programming is an untenable metabolic milieu for productive CD8 T cell anti-tumor responses, as collagen-synthesizing macrophages consume environmental arginine, synthesize proline, and secrete ornithine that compromises CD8+ T cell function. Thus, a stiff and fibrotic TME may impede anti-tumor immunity not only by direct physical exclusion of CD8+ T cells, but also via secondary effects of a myeloid mechano-metabolic programming we identified that creates an inhospitable metabolic milieu for CD8+ T cells.

cancer biology↗

bioRxiv2021

Spatiotemporal co-dependency between macrophages and exhausted CD8+ T cells in cancer

T cell exhaustion is a major impediment to anti-tumor immunity. However, it remains elusive how other immune cells in the tumor microenvironment (TME) contribute to this dysfunctional state. Here we show that the biology of tumor-associated macrophages (TAM) and exhausted T cells (Tex) in the TME is extensively linked. We demonstrate that in vivo depletion of TAM reduces exhaustion programs in tumor-infiltrating CD8+ T cells and reinvigorates their effector potential. Reciprocally, transcriptional and epigenetic profiling reveals that Tex express factors that actively recruit monocytes to the TME and shape their differentiation. Using lattice light sheet microscopy, we show that TAM and CD8+ T cells engage in unique long-lasting antigen-specific synaptic interactions that fail to activate T cells, but prime them for exhaustion, which is then accelerated in hypoxic conditions. Spatially resolved sequencing supports a spatiotemporal self-enforcing positive feedback circuit that is aligned to protect rather than destroy a tumor. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/461866v1_ufig1.gif" ALT="Figure 1"> View larger version (65K): org.highwire.dtl.DTLVardef@1fb1c4aorg.highwire.dtl.DTLVardef@fe4571org.highwire.dtl.DTLVardef@1812f76org.highwire.dtl.DTLVardef@5317d5_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2021

MYC promotes immune-suppression in TNBC via inhibition of IFN signaling

Immune checkpoint inhibitor (ICI) treatment has thus far shown limited efficacy in triple-negative breast cancer (TNBC) patients, presumably due to sparse or unresponsive tumor-infiltrating lymphocytes. We reveal a strong correlation between MYC expression and loss of immune signatures in human TNBC. In mouse models of BRCA1-proficient and -deficient TNBC, MYC overexpression dramatically decreased lymphocyte infiltration in tumors, along with immune signature loss. Likewise, MYC overexpression suppressed inflammatory signaling induced by BRCA1/2 inactivation in human TNBC cell lines. Moreover, MYC overexpression prevented the recruitment and activation of lymphocytes in co-cultures with human and mouse TNBC models. Chromatin immunoprecipitation (ChIP)-sequencing revealed that MYC directly binds promoters of multiple interferon-signaling genes, which were downregulated upon MYC expression. Finally, MYC overexpression suppressed induction of interferon signaling and tumor growth inhibition by a Stimulator of Interferon Genes (STING) agonist. Together, our data reveal that MYC suppresses innate immunity and facilitates immune escape, explaining the poor immunogenicity of MYC-overexpressing TNBCs. Statement of SignificanceMYC suppresses recruitment and activation of immune cells in TNBC by repressing the transcription of interferon genes. These findings provide a mechanistic rationale for the association of high MYC expression levels with immune exclusion in human TNBCs, which might underlie the relatively poor response of many TNBCs to ICI.

cancer biology↗

bioRxiv2020

ZipSeq : Barcoding for Real-time Mapping of Single Cell Transcriptomes

Spatial transcriptomics seeks to integrate single-cell transcriptomic data within the 3-dimensional space of multicellular biology. Current methods use glass substrates pre-seeded with matrices of barcodes or fluorescence hybridization of a limited number of probes. We developed an alternative approach, called ZipSeq, that uses patterned illumination and photocaged oligonucleotides to serially print barcodes (Zipcodes) onto live cells within intact tissues, in real-time and with on-the-fly selection of patterns. Using ZipSeq, we mapped gene expression in three settings: in-vitro wound healing, live lymph node sections and in a live tumor microenvironment (TME). In all cases, we discovered new gene expression patterns associated with histological structures. In the TME, this demonstrated a trajectory of myeloid and T cell differentiation, from periphery inward. A variation of ZipSeq efficiently scales to the level of single cells, providing a pathway for complete mapping of live tissues, subsequent to real-time imaging or perturbation.

genomics↗